Context To determine whether journals have improved their disclosure of ethical
protections in clinical trials.

Methods Comparison of clinical trials published before and after 1997 (July
1995 to December 1996 and January 1998 to June 1999) in Annals of Internal Medicine, BMJ, JAMA, The Lancet, and The New England Journal of Medicine. Sixty articles per journal per
period were randomly selected and assessed for rate of reporting on informed
consent and on ethics committee approval.

Results Informed consent was not described in 79 articles (26%) published before
1997 vs 53 (18%) published after 1997 (P = .01),
and ethics committee approval was not mentioned in 93 (31%) before 1997 vs
54 (18%) after 1997 (P<.001). Neither protection
was described in 48 articles (16%) published before 1997 vs 28 (9%) after
1997 (P = .01). In subgroup analyses, those journals
with the worst initial rates generally improved the most. BMJ did not describe informed consent in 25 articles (42%) before 1997
vs 15 (25%) after 1997 (P = .05), and JAMA did
not describe ethics committee approval in 25 (42%) before 1997 vs 13 (22%)
after 1997 (P = .02). BMJ, JAMA, and Annals had the lowest initial rates of
reporting on both protections in the same article, with 25 (42%), 32 (53%),
and 34 (57%), respectively, but improved markedly to 38 (63%), 43 (72%), and
45 (75%) (P = .02, .04, and .03, respectively).

Conclusions Major medical journals have improved their reporting on informed consent
and ethics committee approval; however, 9% of studies still report neither.

The World Medical Association issued the Declaration of Helsinki in
1964,1 with subsequent updates,2
to establish international regulations for human experimentation. It specifically
identified 2 protections: that all participants in trials should understand
the risks, benefits, and alternatives of the experiment and, following this,
should enroll in the trial under their own free will, by giving informed consent,
and that a disinterested party unconnected with the trial, termed the ethics
committee or institutional review board, should have approved the experimental
protocol after assuring its appropriateness of design.

When publishing reports of experimentation, journals have an obligation
to define what constitutes medical research of the highest quality and to
make the ethical conduct of trials a part of this definition. The Declaration
of Helsinki charges journals with this important responsibility, stating:
"Publishers have ethical obligations. . . . Reports of experimentation not
in accordance with the principles laid down in this Declaration should not
be accepted for publication."2 It is essential
that journals inform the public that, to the extent they can determine, the
trials they publish are ethical. They can do so in part by requiring that
all published trials describe informed consent and ethics committee approval.
This duty is supported by the International Committee of Medical Journal Editors
(ICMJE).3

Despite this obligation, in 1997, on the 50th anniversary of the Nuremberg
Code,4 there was growing evidence that journals
were not meeting their commitment to these guidelines.5- 8
Data at the time5 and further documented since9 suggested that articles reporting ethical protections
were of higher methodologic quality than those that did not. The current study
assesses whether journals have improved in their reporting of ethical protections
from the time these deficiencies were highlighted.

METHODS

Clinical trials were studied because their use of interventions makes
the reporting of safeguards particularly important. We selected a random sample
of trials published in the 18 months before and after 1997 (July 1995 to December
1996 and January 1998 to June 1999) in Annals of Internal
Medicine, BMJ, JAMA, The Lancet, and The New England
Journal of Medicine. Clinical trials were defined as studies with interventions
performed at the level of the patient. Brief communications, letters, case
studies, and case series were excluded. Based on data from a pilot study,
we selected a sample size of 300 articles per period (60 per journal) to have
a 2-tailed α of .05 and an 80% power to detect a 10% difference in the
primary outcome measures across the pooled, not individual, journals. A random
numbers table was used to select eligible issues of each journal. All articles
that met the inclusion criteria within a given issue were selected until the
sample size had been reached.

The primary outcome measures were the rates of reporting on informed
consent and ethics committee approval. Our definitions were fulfilled by any
of the following types of descriptions (with examples): (1) informed consent—strict
definition ("the patients gave written informed consent to participate in
the study"), implied ("all subjects gave written consent"), and waived ("the
investigators received approval from their institutional review boards to
use deferred consent"); and (2) ethics committee approval—strict definition
("the study protocol was approved by the hospital's ethics committee"), implied
("ethical approval of the study was obtained from all study sites"), adhered
to the Declaration of Helsinki ("the study was performed according to the
guidelines of the Declaration of Helsinki"), and approved by a government
or professional body ("the protocol was approved by the Office of the Surgeon
General").

One secondary outcome measure was the rate of reporting on the presence,
in each article, of both protections or neither protection. Another outcome
was the rate of reporting on further details of informed consent—the
types identified in the pilot study as written (required by the Declaration
of Helsinki, in the absence of mitigating factors2),
oral, familial, nonfamilial (eg, granted by a legal proxy), witnessed, or
any combination of these. The final secondary outcome was the rate of naming
of ethics committees. Because there is strong evidence of local variation
in the practice and effectiveness of committees,10,11
readers or others may want to know their identity to hold them accountable
for their decisions.

Additional information was collected for use in subgroup analyses on
study participants who belonged to vulnerable populations. The categories
of vulnerable populations were identified through a review of the literature
and government documents12,13
and included children, pregnant women, adults who lacked decision-making capacity
(eg, those with severe dementia), prisoners, and patients with human immunodeficiency
virus, an intensive care unit level of disability, psychiatric disease, or
genetic risks or disease. Data were also gathered on whether articles contained
references to earlier publications on the same study. Such articles may have
a plausible reason for not describing ethical protections, if these were stated
in an earlier article. However, the difficulty of accurately identifying prior
versions of the same article without the benefit of a reference has been well
documented by meta-analysts.14- 16
Therefore, articles that do not mention protections should reference a prior
article that does. We also collected data on the numbers of ethics committees
per article. We then identified the funding source of each study, defined
as industry only (eg, pharmaceutical company), nonindustry only (eg, government
agency, university, or foundation), combination of industry and other, none,
not mentioned, or unclear. Last, we assessed whether each journal's instructions
for authors, published in the first issue of the first month of both study
periods, explicitly stated that articles were required to describe informed
consent or ethics committee approval.

Because the study did not involve human participants or records, it
did not require review by the committee on human research at the University
of California at San Francisco.

Data were gathered by using an extraction instrument developed during
the pilot study. After an author (V.Y.) trained a research assistant (P.G.)
to use the instrument, both tested it on a sample of journal articles that
met the study inclusion criteria but had not been randomly selected for the
study. After discussion of the most common areas of difference in categorization,
both then applied the instrument to 50% of the study sample, with the test
statistic for interrater reliability found to be excellent for all primary
and secondary outcome measures (κ>0.95 for all). Differences were resolved
by discussion. One of the authors (V.Y.) then completed assessments of the
remaining articles. χ2 Analyses were used to test for differences
in the rates of reporting. All analyses were performed by using Microsoft
Excel 98 (Microsoft, Redmond, Wash).

RESULTS

Ethical protections for participants in clinical trials were not reported
in more articles published before 1997 than after (Table 1). Subgroup analyses showed that those journals with the
lowest initial rates of reporting generally improved the most; for example, BMJ with informed consent JAMA with ethics committee
approval. Only 2 journals, The Lancet on informed
consent and Annals on ethics committee approval,
added a new explicit statement regarding ethical protections to their instructions
for authors between study periods.17,18
Both journals demonstrated statistically significant improvements in reporting
on these respective protections. The remaining journals retained roughly the
same explicit statements, or lack thereof, regarding ethical protections.

Table 1. Articles in Which Ethical Protections for Trial Participants Were Not Reported*

Table 1. Articles in Which Ethical Protections
for Trial Participants Were Not Reported*

All journals made progress in describing both informed consent and ethics
committee approval in each article. Those journals with the worst initial
rates improved the most: BMJ, JAMA, and Annals began with rates of 42%, 53%, and 57%, respectively, but improved
markedly to 63%, 72%, and 75% (P = .02, .04, and
.03, respectively). Overall, the rate of reporting improved from 175 of 300
(58%) before 1997 to 221 of 300 (74%) after 1997 (P<.001).

Similarly, fewer articles published after 1997 described neither protection
(Table 2). Of articles on vulnerable
populations, significantly fewer reported neither protection after 1997. The
findings were similar for articles that contained no references to prior articles
on the same study. In both cases, however, each type of article comprised
a large proportion of all articles that mentioned neither ethical protection,
even after 1997.

Of articles that reported informed consent, the majority provided further
description of the type that was obtained (Table 3). Before and after 1997, informed consent was stated to
have been given by someone other than the patient in 27 (9%) and 44 (15%)
of all trials, respectively (P = .03).

Table 3. Type of Informed Consent Described in Articles That Reported the Protection*

Table 3. Type of Informed Consent Described
in Articles That Reported the Protection*

In most articles, the number of ethics committees closely corresponded
to the number of study sites. From before to after 1997, the mean number of
ethics committees per article increased from 6.7 (SD, 13.6; range, 1-135)
to 7.2 (16.4; 1-105), and the 75th percentile from 3 to 4. In contrast, for
articles that met the strict definition of ethical approval, the rate of naming
of ethics committees significantly decreased, from 155 of 198 articles (78%)
to 156 of 234 (67%) (P = .007), possibly because
articles with more than 1 ethics committee had roughly an inverse relationship
between the number of ethics committees and the percentage that was named.
For example, in articles for which the number of ethics committees could be
determined, those that listed 3 or fewer were significantly more likely to
name them than were articles with more than 3, with respective rates of 126
of 142 (89%) vs 27 of 41 (66%) before 1997 (P<.001)
and 122 of 147 (83%) vs 31 of 63 (49%) after 1997 (P<.001).

Regarding study sponsorship, journals consistently improved their reporting
of protections regardless of the type of funding (Table 4). Results were very similar for subgroup analyses performed
by journal.

Table 4. Study Sponsorship and Articles in Which Ethical Protections Were Not Reported*

Table 4. Study Sponsorship and Articles in
Which Ethical Protections Were Not Reported*

Our findings are consistent with the results of prior studies. We found
that roughly 30% of articles published before 1997 did not report informed
consent, and another 30% did not report ethics committee approval. Olson and
Jobe5 reported that 70% of resuscitation articles
published from 1966 to 1994 did not mention informed consent, and 50% did
not mention ethical approval. Rikkert et al6
found that 40% of gerontology trials published from 1993 to 1994 failed to
describe informed consent and 50% ethics committee approval. Matot et al19 reported that 40% of critical care articles from
1994 lacked a statement on informed consent, and 40% had no statement on ethical
review. In articles from 1993 to 1994 in general medical journals, Ruiz-Canela
and Gomez-Gracia20 found no mention of informed
consent in 20% and ethical approval in 30%. Finally, Bauchner and Sharfstein21 reported that only 3% of randomized controlled trials
published on children's health in 1999 reported ethical protection compared
with the 5% rate we found in studies of vulnerable populations published after
1997.

Our study had limited power to detect differences in reporting for individual
journals or other subsets of articles. For example, in Table 1, BMJ experienced an absolute difference
in its rate of reporting of ethical approval of 13% (relative change of 33%)
but the finding was not significant.

We cannot comment on whether similar changes in reporting have occurred
in other types of journals. We also do not know why the improvements have
occurred. Finally, we do not know whether patients have benefited from having
informed consent or ethical approval as safeguards, whether the ethical protections
that are reported are actually being performed (or vice versa), or whether
describing them in articles helps at all. However, as we have stated, transparency
in the reporting of science has inherent benefits.8
The reporting of informed consent and ethics comittee approval attests publicly—in
a forum where the methods can be openly challenged or discussed—to a
minimum level of ethical consideration. Certainly, there is a moral imperative
to assure participants in trials that meticulous attention is being paid to
their safety.

Patients have died in studies that failed to adequately provide protection.22- 24 News stories, not
surprisingly, have questioned the ethical conduct of medical research.22- 24 These events "have
shaken the public's confidence in our ability to govern ourselves."25 In describing the federal government's response,
Shalala26 stated "Clinical researchers and
the institutions that support them must, without exception, maintain the public's
confidence in our work, our competence, and most important, our ethics."

To this end, we recommend that journals publish in their instructions
for authors the explicit requirement that all articles describe informed consent
and ethics committee approval or why these were waived.8
Journals should also assess in-house practices for ways that might further
improve reporting. For their part, authors should provide as many details
as are necessary to accurately describe the implementation of these safeguards.